This research prject is aimed at determining systematically the molecular basis of specificity of pteridines and pteridine-like compounds so that toxic side effects which may occur duing cancer chemotherapy with folate antagonists can be minimized. We intend to study the structure-action relationship of differently substituted pteridines and pteridine-like compounds as cofactors and inhibitors of phenylalanine hydroxylase, tyrosine hydroxylase, and tryptophan hydroxylase, each of which use a pteridine, tetrahydrobiopterin, as cofactor. The effects of the compounds will also be determined on: (1) dihydropteridine reductase, the enzyme which in vivo regenerates tetrahydrobiopterin during the reaction of the aromatic amino acid hydroxylases; and (2) dihydrofolate reductase, which in addition to converting the dietary form of folic acid to the active cofactor form, tetrahydrofolic acid, also converts the dietary form of biopterin to the cofactor form, tetrahydrobiopterin. The aappropriately substituted pteridines, if not available, will be synthesized, so that the molecular requirements for binding and for cofactor or substrate activity can be determined with each of the above enzymes. With a detailed knowledge of the functioning and specificity of pteridine coenzymes, the production of new chemotherapeutic agents with greater selectivity will become possible.